Multiple cancers are driven by aberrant signaling through ErbB, or HER, family members. Recent studies have indicated that HER2-HER3 heterodimers can play a central role in tumorigenesis. HER3 is a preferred dimerization partner for HER2, which has no known ligand and is constitutively active. Although HER3 has very low intrinsic kinase activity, there are six phosphorylation dependent binding sites for PI3K on the cytosolic tail of this receptor. Consequently, HER2-HER3 heterodimers are the most effective activators identified to date of the PI3K/Akt pathway through both ligand-independent and ligand-dependent signaling. Ligand-dependent activation of HER3 involves the binding of heregulin or other ligands to induce a conformational switch in the dimerization arm, driving heterodimer formation with kinase competent partners such as HER2 or EGFR. Consistent with HER3 as a driver of tumorigenesis, loss of HER3 expression in breast cancer cells results in reductions in both PI3K/Akt signaling and proliferation (Lee-Hoeflich S T, Crocker L, Yao E, Pham T, Munroe X, Hoeflich K P, et al. A central role for HER3 in HER2-amplified breast cancer: implications for targeted therapy. Cancer Res 2008; 68:5878-87; and Holbro T, Beerli R R, Maurer F, Koziczak M, Barbas C F, 3rd, Hynes N E. The ErbB2/ErbB3 heterodimer functions as an oncogenic unit: ErbB2 requires ErbB3 to drive breast tumor cell proliferation. Proc Natl Acad Sci USA 2003; 100:8933-8). Further, modeling studies demonstrate that HER3 represents a central node in PI3K/Akt signaling. In conjunction with the limited efficacy of solely targeting HER2 with monotherapies such as trastuzumab these observations have motivated the development of therapeutics targeting HER3 and/or HER2-HER3 heterodimers. Recent data indicates that the targeting of this axis with antibodies is less effective in the presence of heregulin, which is expressed in either autocrine or paracrine fashion in many tumor types.
As an alternative to targeting HER family members with antibodies, the use of small molecule inhibitors of the tyrosine kinase activity of EGFR and/or HER2, or of the downstream kinase, PI3K, has attracted much interest. However, these inhibitors can lead to tumor escape due to upregulation of compensatory signaling pathways and complex cross-regulatory networks involving negative feedback loops. For example, the delivery of lapatinib, a tyrosine kinase inhibitor (TKI) that targets both EGFR and HER2, results in upregulation of HER2 and HER3 expression. Lapatinib resistance pathways can also include activating mutations of PI3K, and the inhibitory effects of lapatinib can be dampened by the presence of the HER3 ligand, heregulin. (Sergina N V, Rausch M, Wang D, Blair J, Hann B, Shokat K M, et al. Escape from HER-family tyrosine kinase inhibitor therapy by the kinase-inactive HER3. Nature 2007; 445:437-41; Wilson T R, Fridlyand J, Yan Y, Penuel E, Burton L, Chan E, et al. Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors. Nature 2012; 487:505-9 and Li Q, Ahmed S, Loeb J A. Development of an autocrine neuregulin signaling loop with malignant transformation of human breast epithelial cells. Cancer Res 2004; 64:7078-85). This suggests that lapatinib in combination with antibodies or bispecifics that bind to HER3 might provide an effective route for therapy, particularly for tumors involving autocrine or paracrine heregulin loops that can result in limited efficacy of monotherapies.
Related to the limited therapeutic efficacy of TKIs such as lapatinib that inhibit EGFR and HER2 activation, HER3 can associate with other activating receptors such as cMET and insulin-like growth factor type I receptor I/insulin receptor substrate-1. A possible strategy to extinguish HER3-PI3K signaling could therefore be to inhibit multiple potential HER3 partners.
Thus, there is a need for the generation of improved therapeutics directed towards ligand-dependent activation of HER3.